About 1-3% of all women undergo precocious menopause, either never going through menarche or stopping menstruation by the mid-30s, rather than reaching the standard reproductive lifespan at about 50. A fraction of such instances of early-onset premature ovarian failure (POF) is genetic. A single locus on chromosome 3 is implicated in several families and in several isolated individuals with translocations or deletions that interrupt the DNA in that region. A much larger group of translocations have been reported on the X chromosome, centering on a critical region of the long arm. There we have shown that based on the physical map we had constructed, there are at least 35 distinct X chromosome loci at which translocations can produce POF. To see if the associated translocations cause POF by the interruption of specific genes involved in follicle formation or stability, we have begun further molecular analyses of the sequences spanning translocation breakpoints. For the chromosome 3 locus and for two X chromosome loci, breakpoints have been localized to within 200 kb, and substrate clones have been chosen for long-range sequencing analysis. A combination of computer-aided sequence analysis and cDNA searches is being used to look for gene candidates that can be determining for female reproductive lifespan. - Menopause; X chromosome breakpoints; mapping; sequence analysis; fetal development; X- inactivation